Designing an adaptive phase II/III trial to evaluate efficacy, safety and immune correlates of new TB vaccines in young adults and adolescents.

This article summarises the consensus arrived at a meeting of South African and international stakeholders on specific late phase clinical trial design issues integrating the investigation of immune correlates as an integral part of a phase III protocol for a preventative TB vaccine in an adolescent/adult population. The challenge ahead is to optimize the planning for phase 3 TB vaccine preventative trials, under resource constraints, given that there are no known correlates of protection to shorten and increase the efficiencies of efficacy trials. An adaptive, multi-arm, group sequentially designed trial protocol is proposed incorporating design features that address uncertainties arising from both advances in the field and dynamic study populations and disease states. Such a design allows modifications that protect research subjects, save time, and maximize the impact of scarce financial resources. Further, the protocol underwent joint review by regulators from several African nations at a meeting of the African Vaccine Regulatory Forum (AVAREF), a regional regulatory harmonization initiative, and recommendations are included.

The effects of smoking on estradiol metabolism.

Smoking remains a major health problem especially among women and it influences estrogen metabolism and the risk for multiple estrogen sensitive outcomes. Many indirect effects of smoking exist through the ability of the by-products to modify a variety of drugs, enzymes, and hormones. The results of several in vitro studies have shown that constituents of cigarette smoke have significant effects on production and metabolism of estrogens. In some cases, such as osteoporosis and endometrial cancer, smoking appears to attenuate the effects of estrogen. However, for other outcomes such as breast cancer, venous thromboembolic events (VTE), and coronary heart disease (CHD), the relationship between smoking and estrogen exposure is less defined. Based on the preponderance of evidence, smokers are likely to require higher doses of hormone replacement therapy (HRT) to achieve comparable clinical effect to that observed in nonsmokers. However, uptitrating the dose of HRT in smokers to achieve a desired systemic level or clinical response may simultaneously increase risk for adverse effects that are primarily driven by hepatic rather than systemic exposure. The healthy benefits from smoking cessation should be expressed to women who choose to use HRT, and every effort should be made to encourage them to stop smoking so that they can be effectively treated with the lowest possible dose of HRT.

Superheating and supercooling of vortex matter in a Nb single crystal: direct evidence for a phase transition at the peak effect from neutron diffraction.

We report the first observation of a striking history dependence of the structure function of vortex matter in the peak effect regime in a Nb single crystal by using small angle neutron scattering combined with in situ magnetic susceptibility measurements. Metastable phases of vortex matter, supercooled vortex liquid and superheated vortex solid, have been identified. We interpret our results as direct structural evidence for a first-order vortex solid-liquid transition at the peak effect.

Using satellite imagery to assess large-scale habitat characteristics of adirondack park, new york, USA.

Satellite imagery is a useful tool for large-scale habitat analysis; however, its limitations need to be tested. We tested these limitations by varying the methods of a habitat evaluation for white-tailed deer (Odocoileus virginianus) in the Adirondack Park, New York, USA, utilizing harvest data to create and validate the assessment models. We used two classified images, one with a large minimum mapping unit but high accuracy and one with no minimum mapping unit but slightly lower accuracy, to test the sensitivity of the evaluation to these differences. We tested the utility of two methods of assessment, habitat suitability index modeling, and pattern recognition modeling. We varied the scale at which the models were applied by using five separate sizes of analysis windows. Results showed that the presence of a large minimum mapping unit eliminates important details of the habitat. Window size is relatively unimportant if the data are averaged to a large resolution (i.e., township), but if the data are used at the smaller resolution, then the window size is an important consideration. In the Adirondacks, the proportion of hardwood and softwood in an area is most important to the spatial dynamics of deer populations. The low occurrence of open area in all parts of the park either limits the effect of this cover type on the population or limits our ability to detect the effect. The arrangement and interspersion of cover types were not significant to deer populations.

Orosensory factors in the ingestion of corn oil/sucrose mixtures by the rat.

The experiments reported here were designed to study the orosensory factors contributing to the ingestion of sucrose/corn oil mixtures. When a flavor aversion was conditioned to the sucrose/corn oil mixture, the subsequent aversion to the mixture strongly generalized to the corn oil but very little to the sucrose. Rats conditioned with corn oil show a more profound aversion to the sucrose/corn oil mixture than rats conditioned with sucrose, indicating that the salient feature of the sucrose/corn oil mixture is the oil. Aversion to the sucrose/corn oil mixture does not generalize to a sucrose/mineral oil mixture, giving evidence that the textural aspects of the oil do not play a major role in its perception. This flavor aversion to the mixture is further illustrated in very short-term tests where postingestive factors are minimized, indicating a role for the gustatory system in the detection of the sucrose/corn oil mixture. Preliminary experiments are reported where conditioning tests were run with mixtures of sucrose and linoleic acid, one of the fatty acids that is possibly derived from a breakdown of the corn oil in the oral cavity by lingual lipase from von Ebner's Gland.

Comparison of two concentrations of amphotericin B bladder irrigation in the treatment of funguria in patients with indwelling urinary catheters.

The efficacy of amphotericin B bladder irrigation at two concentrations was studied. Patients with funguria (> or =15,000 colony-forming units of yeast per milliliter of urine), an indwelling urinary catheter, and a physician order for amphotericin B continuous bladder irrigation were randomly assigned to receive 10 or 50 mg of amphotericin B per liter of sterile water as a continuous irrigation for 72 hours at the rate of 42 mL/hr. Before the bladder irrigation began, the indwelling catheter was changed to a three-way catheter. Repeat urine cultures were performed 24 hours after the irrigation was discontinued. A total of 28 patients were enrolled from November 1993 to May 1995. The rate of eradication of the infection was 100% in the 50-mg/L group and 67% in the 10-mg/ L group. Subject enrollment was stopped prematurely because all the treatment failures occurred in the 10-mg/L group. Dose was the only variable significantly associated with outcome. Bladder irrigation with amphotericin B was more effective when the drug concentration was 50 mg/L rather than 10 mg/L.

Mouse monoclonal antibody bearing a VH framework region determinant similar to a rabbit VHa1 allotope.

A monoclonal antibody (mAb 6B8.2) was derived from a mouse immunized with rabbit anti-a1 VH allotype antibody. 6B8.2 specifically reacts with a subpopulation (19-44%) of anti-a1 antibodies from each of 17 a1-immunized rabbits, but does not react with normal rabbit Ig or rabbit antibody to other rabbit allotypes. 6B8.2 also reacts with guinea-pig anti-a1 antibodies and a mouse anti-a1 mAb. Surprisingly, 6B8.2 does not represent an anti-idiotype antibody but rather appears to express an 'a1-like' epitope in the VH framework region of the molecule. This conclusion is supported by Western blot analysis and immunoelectron microscopy of 6B8.2 in complex with rabbit anti-a1 antibody. These data reveal that the determinant recognized by anti-a1 antibody is localized to the H-chain and is not at the distal tip of the mAb. Thus, the location of the 'a1-like' determinant of 6B8.2 appears similar, if not identical, to the location of the a1 determinant on Ig molecules from rabbit and goat, suggesting that a framework region a1-like determinant may be widespread and thus evolutionarily conserved in mammals.

In vivo response time of transcutaneous oxygen measurement to changes in inspired oxygen in normal adults.

We examined the in vivo response time of transcutaneous oxygen measurement (PtcO2) to a step increase (100 per cent oxygen) or decrease (air) of inspired oxygen in five normal adults (age 27 +/- SD 4.5 years). The PtcO2 electrode was placed on the upper chest (sensor temperature 44 degrees C). The mean +/- SEM 63 and 95 per cent response times of PtcO2 to a step increase in inspired oxygen were 2.9 +/- 0.2 and 6.8 +/- 0.2 and to a step decrease were 2.4 +/- 0.2 and 5.1 +/- 0.3 minutes. The 63 and 95 per cent response times for the pulmonary washin of oxygen were 1.0 and 2.6 minutes and washout were 0.8 and 2.3 minutes. We conclude that the in vivo response time of the PtcO2 is reproducible but substantially longer than that of the pulmonary washin and washout times and inadequate to monitor rapid changes in arterial oxygenation during anaesthesia, perioperative period or sleep in adults.

Population genetic structure of Nantucket pine tip moth.

Variation at polymorphic isozyme loci was analyzed in Nantucket pine tip moth (NPTM) populations from 5 geographic locations. At the North Carolina location, populations representing 3 generations at 3 local sites were also studied. Four of the loci investigated (LAP, MDH, α-GPDH and AK), although variable, had few alleles per locus (3-5) and few differences among populations in allele frequencies. At each locus, all populations had the same allele at a high frequency.At the PGM locus, fifteen alleles were identified and allelic frequencies varied among populations. At least eight alleles were present within a population and, in most populations, two or more alleles had high frequencies that differed among populations. An excess of homozygotes over Hardy-Weinberg expectations was found for 7 out of the 10 populations studied, indicating the probable existence of some form of inbreeding structure or populational subdivision within sampled stands.Joint consideration of the results observed for PGM and the other four loci is counterindicative of neutrality at all loci and strongly indicative of genetic differentiation among locally disjunct populations.

Brown's syndrome. An unusual manifestation of rheumatoid arthritis.

Two patients presented with an ocular complication of rheumatoid arthritis that was extraocular in location. Clinical manifestations include vertical diplopia, an intermittent nature, a clicking sensation, and apparent inferior oblique palsy. A stenosing tenovaginitis of the superior oblique tendon and its sheath is the probable underlying pathologic mechanism.

Identification, evaluation, therapy, and follow-up for children with vocal nodules in a public school setting.

This paper describes procedures used by speech and otorhinolaryngology specialists in the Independent School District of Carrollton and Farmers Branch, Texas, to identify, evaluate, treat, and follow up children with voice disorders and presents some initial findings resulting from the use of these procedures. In the identification process, 34 children were found to have vocal nodules, of which 31 children received treatment and underwent appropriate follow-up. After two months of voice therapy, 21 (68%) of the children exhibited reduced nodule size and seven (23%) exhibited normal larynges. Following six months of therapy, 26 (84%) children exhibited reduced nodule size, and 20 (65%) had normal larynges.